Methods and devices for ex vivo irradiation of autologous coronary bypass conduit

ABSTRACT

Fibrointimal proliferation, neointimal hyperplasia and other vascular lesions or injuries are reduced by ex vivo irradiation of the autologous coronary bypass conduit, especially the saphenous vein, as an adjunct in cardiovascular surgery or other treatment, in anyone of a variety of suitable devices.

BACKGROUND OF THE INVENTION

[0001] It is known that the human body's healing response to injurytypically includes the formation of what is commonly called scar tissue.A microscopically similar response also occurs within the transplantedvascular tissue of a person following transplantation of the saphenousvein into the coronary artery or peripheral vascular circulation toserve as a bypass.

[0002] One area of the vascular system of particular concern withrespect to such injuries is saphenous veins that are used to providebypass conduits for obstructed coronary arteries and also for obstructedperipheral arteries. Partial and even complete blockage of saphenousvein bypass grafts by the sequential ant overlapping processes ofthrombosis (formation of blood clots), fibrointimal hyperplasia (smoothmuscle cell overgrowth) or formation of an atherosclerotic plaque uponthe inner lining of the already thickened saphenous vein segment is awell known and frequent medical problem following coronary artery bypassgrafting.

[0003] Occlusion of coronary artery bypass grafts occurs in more thanfifty percent of saphenous vein grafts by the time the graft is tenyears old, affecting the majority of patients with saphenous vein bypassgrafts.

[0004] In conventional treatment, such blockages may be treated usingatherectomy devices, which mechanically remove the plaque; hot or coldlasers, which vaporize the plaque; stents, which hold the artery open;and other devices and procedures which have the object of allowingincreased blood flow through the bypass conduit. The most common suchprocedure is the percutaneous transluminal coronary angioplasty (PTCA)procedure, more commonly referred to as balloon angioplasty. In thisprocedure, a catheter having an inflatable balloon at its distal end isintroduced into the coronary artery or saphenous vein bypass graft, theuninflated balloon is positioned at the stenotic site and the balloon isinflated. Inflation of the balloon disrupts and flattens the plaqueagainst the vessel wall, and stretches the arterial or venous wall,resulting in enlargement of the intraluminal passageway and increasedblood flow. After such expansion, the balloon is deflated and theballoon catheter removed.

[0005] However, all of the above conventional remedies for vascularocclusion are performed after the vein is sewn into the coronary arterysystem and after the problem of vascular occlusive disease has developedand become a problem for the patient. By contrast, the present inventionprovides methods and devices to prevent such blockage from occurring, byirradiation of the bypass graft during the bypass graft surgicalprocedure.

[0006] Smooth muscle cell migration and proliferation are stimulated inseveral ways during transplant of vascular tissue such as saphenousveins, including mechanical trauma, and baurotrama. Such stimulationalso occurs from denudation of the endothelium, and from mitogenicproliferative factors, such as platelet-derived growth factor,fibroblast growth factors, and epidermal growth factor. These influencesinitiate the body's own natural repair and healing process. During thishealing process, vascular smooth muscle cells migrate into the intimaand prolferate. The formation of scar tissue by smooth muscleproliferation, also known as fibrointimal hyperplasia, is believed to bea major contributor to the occlusion of saphenous vein bypass graftsfollowing placement of vein grafts into the aortocoronary circulation.

[0007] Prior efforts to inhibit occlusion of saphenous vein grafts haveincluded optimal antiplatelet therapy with the combination of aspirinand dipyridamole, which reduced the rate of occlusion from about 25% atone year to about 11%. However, the improvement relating to theprevention of thrombosis had no identifiable beneficial effect upon theprocess of fibrointimal proliferation. Fibrointimal proliferationresults in about 25% lumenal narrowing by the end of one year in allvein graft segments.

[0008] Although radiation therapy has shown promise, particularly ininhibiting neotintimal hyperplasia within the in vivo arterialcirculation, the devices available for delivery of radiation sourceshave been limited to treating a segment of vascular tissue within thepatient, and have not been applied to treatment of vascular tissue beingtransplanted from one site of the body to another while it is outside ofthe patient's body.

[0009] The present invention includes ex vivo methods of treatingvascular tissue, e.g., saphenous vein coronary artery bypass grafts,with endovascular irradiation, particularly beta irradiation. Thismethod is particularly suitable for ex vivo applications. The inventorhas also developed devices suitable for such methods, including sterilesleeves for endovascular positioning of the radiation source, housingsfor the radiation sources, and a radiation seed safe module for thepurpose of shielding and storing the radiation source, said modulecontaining radiation pellets for insertion into the sleeve lumen orcavity.

[0010] The methods and devices of the present invention are suitable forreducing fibrointimal proliferation or neointimal hyperplasia, vascularlesions that commonly occur in the treatment of cardiovascular disease,e.g. balloon angioplasty, coronary bypass surgery. The present inventionis also suitable for achieving a clinically significant decrease in themorbidity and mortality resulting from SVG occlusions, particularly inview of the large number of patients at risk. About 220,000 patientsundergo each year coronary artery bypass surgery with a saphenous veinas the bypass conduit, of which about 22,000 would substantially benefitfrom the methods and devices of the present invention.

BRIEF DESCRIPTION OF THE INVENTION

[0011] The present invention is directed to devices and methods fordelivering one or more treating elements, such as a radiation source,into or outside of a suitable sleeve or elongated means, upon which isplaced a segment of a suitable graft, e.g., saphenouse vein. The veinhas been removed from the patient's leg or arm and divided into one ormore tubular segments for use as bypass material. The vein is mounted onthe sleeve or elongated means. It is then subjected to radiationeffective to reduce or inhibit overgrowth of vascular repair tissue, byexposure to a radiation source within the lumen of the graft or outsideof the graft. Having irradiated the graft, it is then implanted backinto the patient before finishing the bypass surgery.

[0012] Methods of irradiating saphenous coronary bypass conduits is alsodisclosed, including a suitable apparatus for ex vivo applications. Onepreferred method and apparatus of the present invention involvescoronary bypass surgery with an autologous saphenous vein graft, using⁹⁰Sr seeds as a beta radiation source.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 schematically shows a sterile sleeve 1 with adaptor 3,according to a preferred embodiment of the present invention.

[0014]FIG. 2A schematically shows a sterile sleeve of FIG. 1 with agraft in position for endovascular delivery of radiation.

[0015]FIG. 2B schematically shows a sterile sleeve of FIG. 1 with meshinstead of a balloon, according to a preferred embodiment of the presentinvention.

[0016]FIG. 2C schematically shows a sterile sleeve of FIG. 2B with meshexpanded to fit a vein graft to be placed thereon, according to apreferred embodiment of the present invention.

[0017]FIG. 2D schematically shows a sterile sleeve of FIG. 1 withfilaments intended to bow out to fit a vein graft to be placed thereon,according to a preferred embodiment of the present invention.

[0018]FIG. 2E schematically shows a sterile sleeve of FIG. 2D withfilaments bowed out, according to a preferred embodiment of the presentinvention.

[0019]FIG. 3 schematically shows a radiation seed safe module withadaptor, according to a preferred embodiment of the present invention.

[0020]FIG. 4 schematically shows a total assembly, according to apreferred embodiment of the present invention, comprising sterilesleeve, with graft in place, the radiation seed safe module, radiationshield, with continuous inner lumen for driving radiation seeds into thelumen of the sleeve.

[0021]FIG. 5 schematically shows a beta source control device, accordingto a preferred embodiment of the present invention, with sleeve inplace.

[0022]FIG. 6 schematically shows one form of a control unit or controlbox for positioning radiation pellets in ex vivo applications, accordingto a preferred embodiment of the present invention.

[0023]FIG. 7 schematically shows is a sterile sleeve attached directly,without adaptor, to a radiation seed safe module with plunger forinsertion of radiation seeds through the lumen of the sleeve, accordingto a preferred embodiment of the present invention.

[0024]FIG. 8 schematically shows the device of FIG. 7 with housingacting as a radiation shield.

[0025]FIG. 9A schematically shows, according to one embodiment of thepresent invention, a cylinder with attached radiation sources forexovascular delivery of a radiation dose to a graft.

[0026]FIG. 9B schematically shows, according to one embodiment of thepresent invention, a cross section of the cylinder depicted in FIG. 9A,and a cross section of the attached radiation source.

[0027]FIG. 10 schematically shows, according to one embodiment of thepresent invention, a cylinder of FIG. 9A with pin and balloon placedtherein. ABBREVIATIONS AND DEFINITIONS CABG Coronary Artery Bypass GraftConduit graft Vessel graft, which is a vein or artery FIH FibrointimalProliferation, also known as Neointimal Hyperplasia. An exuberant orexcessive growth of reparative tissue in the vessel in response toinjury. Gy Gray, a unit of absorbed radiation dose, i.e. the absorbeddose when the energy per unit mass imparted to matter by ionizingradiation is 1 joule per kilogram. 10⁻² Gy = rad (rd). IMA InternalMammary Artery NIH Neointimal Hyperplasia, also known as NeointimalProliferation. PTCA Percutaneous Transluminal Coronary Angioplasty SVGSaphenous Vein Graft

DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention relates to methods and devices forinhibition of overgrowth of vascular tissue, e.g., fibrointimalproliferation or neointimal hyperplasia, in transplanted vasculartissue. The treatments described in the present invention occur duringthe surgical grafting procedure, but their effect is often not detectedclinically for many months after successful completion of the surgery.The present invention also relates to revascularization procedures suchas bypass grafting of the femoral artery to the popliteal artery,aortofemoral bypass grafting procedures utilizing transplantedautologous vascular tissues, such as the autologous saphenous vein.

[0029] The present invention relates to a method of reducing overgrowthof vascular repair tissue, e.g., fibrointimal proliferation orneointimal hyperplasia, in autologous coronary bypass conduit grafts,comprising the steps of:

[0030] (a) providing a graft harvested ex vivo from a mammal;

[0031] (b) subjecting the graft to irradiation with a dose effective forreducing fibrointimal proliferation or neointimal hyperplasia, to give atreated graft; and

[0032] (c) surgically implanting the treated graft into same mammal.

[0033] In one embodiment of the method of the present invention, thecoronary bypass conduit graft is removed from the long saphenous vein,the short saphenous vein, the cephalic vein, the brachiocephalic vein,or radial artery.

[0034] In another embodiment of the method of the present invention, theirradiation is beta irradiation from within the lumen of the graft.

[0035] In another embodiment of the method of the present invention, theirradiation is X irradiation from a micro X-ray source within the lumenof the graft.

[0036] In another embodiment of the method of the present invention, theirradiation is from the gamma emitting radionuclide ¹²⁵I.

[0037] In another embodiment of the method of the present invention, themammal is a human.

[0038] In another embodiment of the method of the present invention, thedose is limited to a range of between about 1.0 Gy and about 60.0 Gy.

[0039] In another embodiment of the method of the present invention, thedose is limited to a range of between about 3.0 Gy and about 30.0 Gy.

[0040] In another embodiment of the method of the present invention, thedose is limited to a range of between about 6.0 Gy and about 20.0 Gy.

[0041] In another embodiment of the method of the present invention, theradiation source is ⁹⁰Sr.

[0042] One specific embodiment of the present invention is a method ofreducing fibrointimal proliferation or neointimal hyperplasia inautologous coronary bypass vein grafts, comprising the steps of:

[0043] (a) providing a vein harvested ex vivo from a human, said veinselected from the long saphenous vein and the short saphenous vein;

[0044] (b) subjecting the vein to beta irradiation from within the lumenof the vein, with a dose effective for reducing fibrointimalproliferation or neointimal hyperplasia, said dose ranging from betweenabout 6.0 Gy and about 20.0 Gy of ⁹⁰Sr, to give a treated vein; and

[0045] (c) surgically implanting the treated vein into same human.

[0046] The present invention also relates to a device for irradiating exvivo autologous coronary bypass conduit grafts of a mammal, comprising

[0047] (a) a sterile sleeve insertable ex vivo into the lumen of thegraft; and

[0048] (b) a radiation source capable of delivering a dose effective forreducing fibrointimal proliferation or neointimal hyperplasia in thegraft, said source insertable into said sleeve for endovascular deliveryof the radiation dose to the graft.

[0049] In one embodiment of the device of the present invention, thecoronary bypass conduit graft is removed from the long saphenous vein,the short saphenous vein, the cephalic vein, the brachiocephalic vein,or radial artery.

[0050] In another embodiment of the device of the present invention, theradiation source produces beta irradiation.

[0051] In another embodiment of the device of the present invention, theradiation is X rays from a micro X-ray source.

[0052] In another embodiment of the device of the present invention, theradiation source is the gamma emitting radionuclide ¹²⁵I.

[0053] In another embodiment of the device of the present invention, themammal is a human.

[0054] In another embodiment of the device of the present invention, theradiation source delivers a dose of between about 1.0 Gy and about 60.0Gy.

[0055] In another embodiment of the device of the present invention, theradiation source delivers a dose of between about 3.0 Gy and about 30.0Gy.

[0056] In another embodiment of the device of the present invention, theradiation source delivers a dose of between about 6.0 Gy and about 20.0Gy.

[0057] In another embodiment of the device of the present invention, theradiation source is ⁹⁰Sr.

[0058] The present invention also relates to a device for irradiating exvivo an autologous coronary bypass vein graft in a human, comprising

[0059] (a) a sterile sleeve insertable ex vivo into the lumen of thevein graft; and

[0060] (b) a radiation source capable of delivering a dose effective forreducing fibrointimal proliferation or neointimal hyperplasia in thevein graft, said source comprising radiation seeds of ⁹⁰Sr, said sourceinsertable into said sleeve for endovascular delivery of the radiationdose to the vein graft, said dose ranging from between about 6.0 Gy andabout 20.0 Gy.

[0061] The present invention also relates to a second device forirradiating ex vivo an autologous coronary bypass conduit graft of amammal, comprising

[0062] (a) a sterile sleeve for holding ex vivo the graft during itsirradiation, wherein the sleeve is insertable ex vivo into the graftlumen;

[0063] (b) a radiation seed safe module attached, with or without fixedor detachable adaptor means, to the sleeve with locking or screwingmeans, said module containing a radiation source capable of being driveninto and through the lumen of the sterile sleeve to provide endovasculardelivery of a radiation dose to the graft, said radiation dose suitablefor reducing fibrointimal proliferation or neointimal hyperplasia in thegraft; and

[0064] (c) a radiation shield attached at or near the junction of thesleeve and the radiation seed safe module.

[0065] In one embodiment of the second device of the present invention,the coronary bypass conduit graft is removed from the long saphenousvein, the short saphenous vein, the cephalic vein, the brachiocephalicvein, or radial artery.

[0066] In another embodiment of the second device of the presentinvention, the radiation source produces beta irradiation.

[0067] In another embodiment of the second device of the presentinvention, the radiation is X-rays from a micro X-ray source.

[0068] In another embodiment of the second device of the presentinvention, the radiation comes from the gamma emitting radionuclide¹²¹I.

[0069] In another embodiment of the second device of the presentinvention, the mammal is human.

[0070] In another embodiment of the second device of the presentinvention, the radiation source comprises radiation seeds of ⁹⁰Sr.

[0071] In another embodiment of the second device of the presentinvention, the radiation dose is limited to the range between about 1.0Gy and about 60.0 Gy.

[0072] In another embodiment of the second device of the presentinvention, the radiation dose is limited to the range between about 3.0Gy and about 30.0 Gy.

[0073] In another embodiment of the second device of the presentinvention, the radiation dose is limited to the range between about 6.0Gy and about 20.0 Gy.

[0074] The present invention also relates to a device for betairradiating ex vivo an autologous vein graft of a human, comprising

[0075] (a) a sterile sleeve for holding ex vivo the graft during itsirradiation, wherein the sleeve is insertable ex vivo into the graftlumen;

[0076] (b) a radiation seed safe module attached, with or without fixedor detachable adaptor means, to the sleeve with locking or screwingmeans, said module containing a radiation source comprising one or moreradiation seeds of ⁹⁰Sr capable of being driven into and through thelumen of the sleeve to provide endovascular delivery of a radiation doseto the graft, said radiation dose suitable for reducing fibrointimalproliferation or neointimal hyperplasia in the graft, said radiationdose between about 8.0 Gy and about 20.0 Gy; and

[0077] (c) a radiation shield attached at or near the junction of thesleeve and the radiation seed safe module.

[0078] The present invention also relates to a third device forirradiating ex vivo autologous coronary bypass conduit grafts of amammal, comprising

[0079] (a) a sterile slender elongated means insertable ex vivo into thelumen of the graft, for the purpose of mounting and positioning thegraft;

[0080] (b) a cylinder with one or more attached radiation sources, saidelongated means with mounted graft insertable into the inside of thecylinder for exovascular delivery of the radiation dose to the graft,said radiation sources capable of delivering a dose effective forreducing fibrointimal proliferation or neointimal hyperplasia in thegraft.

[0081]FIG. 1 shows schematically a sterile disposable sleeve 1,according to a preferred embodiment of the present invention. Sleeve 1may be formed of any desired material, including plastic or otherpolymeric material, preferably plastic. The sleeve 1 is optionallycovered with balloon 4. The sleeve 1 without balloon varies betweenabout 1 and about 8 mm in outer diameter. It may be inserted by thesurgeon into the coronary bypass conduit, e.g., the saphenous veinsegment. The balloon 4 is placed to account for varying inner diametersof the bypass conduit lumen, in order to enhance uniform irradiation ofthe graft. The balloon 4 can be inflated according to the size of thegraft lumen, and the pressure within the balloon can optionally bemonitored with a conventional manometer. The sleeve 1 is sealed closedat one end and is open at the other so that the shielded radiation,e.g., strontium, source can be inserted into the sleeve after the bypassconduit graft is placed upon it. The sleeve 1 can be screw-locked (luerlok type) if desired into a sterile 1.2 cm thick clear plastic“test-tube” structure that protects the vein during the procedure, andattenuates any beta particles that pass through the vein segment duringthe radiation treatment (not shown). Optionally, the irradiationprocedure can be performed with a hinged clear plastic hood 29 thatattenuates beta rays, such as that exemplified in FIG. 8. The clearplastic hood 29 is typically at least about 1.2 cm thick.

[0082] Lumen 2 of the sleeve 1 is a hollow cavity inside of the sleeve1, with the purpose of providing a way to insert, inside the vein, aradiation source, such as radiation seeds, for endovascular delivery ofradiation. Typically lumen 2 is a cavity with a uniform inner diameter,formed, for example, by drilling at one end of an elongated means toform the sleeve 1.

[0083] Placement of a graft 5 on the plastic sleeve 1 is shownschematically in FIG. 2A, according to a preferred embodiment of theinvention. The graft is shown in cross-section. A pressure measuringdevice, e.g., a manometer, is also shown for balloon 4. It will beunderstood from this and other figures that the size and pressure of theballoon are adaptable to the size of the particular graft about to bereimplanted into its autologous host. Alternatively, the balloon 4 maybe manufactured to inflate to a predetermined external diameter andlength. In some cases, a balloon is not necessary to the method andprocedure of the present invention, e.g., a solid plastic rod with lumenor cavity for radiation source may be sufficient.

[0084] Instead of a balloon, appropriate placement of mesh or filamentsare readily employed to position the vein to receive a substantiallyuniform radiation dose. For example, FIG. 2B schematically shows,according to one embodiment of the present invention, a sterile sleeve 1with mesh 36 bounded by a fixed collar 37 and a slidable collar 38. Toexpand the mesh 36, the slidable collar 38 is moved toward the fixedcollar 37. An illustration of an expanded mesh is schematically shown inFIG. 2C, according to one preferred embodiment of the present invention,with slidable collar 38 moved away from the distal end of sterile sleeve1. To give an example of the filaments, FIG. 2C schematically shows,according to one embodiment of the present invention, a sterile sleeve1.

[0085] A radiation seed safe module 34, depicted schematically in FIG.3, houses radiation seeds 8 in a detachable safe 6, prior toendovascular delivery of the radiation seeds 8 into the lumen 2 of thesleeve 1. See also FIG. 2. An end cap 7, which can be metallic or formedof other desired material, protects handlers from unwanted irradiationwhen the adaptor 3 or other attachment means is removed. An internalsource stop 9 prevents retraction of the radiation source, e.g., seeds,beyond and outside of the detachable safe 6. Within the lumen 2 of thedetachable safe 6, is an outer cable sleeving 11, and an inner cable 10,typically epoxied. The adaptor 3 when present, may have a threadedfitting 33 for attachment to the sterile sleeve 1, or it may lock ontothe sterile sleeve 1.

[0086] There are a variety of ways to attach sleeve 1 to the detachablesafe 6. The sleeve 1 can be directly attached to the detachable safe 6as illustrated schematically in FIGS. 7 and 8. Alternatively, the sleeve1 can be attached to the base and pedestal 30, to which is attached thedetachable safe 6, such that a lumen 2 forms a continuous passageway toallow insertion of radiation seeds into the lumen 2 of the sleeve 1, asillustrated in FIG. 4. Another means of attachment is with an adaptor 3that is fixed or detachable, as illustrated in FIGS. 1-3. The attachmentmeans in each such situation includes, but is not limited to, anypermanent or detachable fitting, such as a threaded fitting, screw lock,luer lok, luer slip, John Guest® Quick Disconnect Fitting, Keck®connector, a barbed fitting, a flared fitting, a combination of a flaredfemale end and male end, an Asti Teflon® connector, a loose collarcapable of tightening the junction when screwed tight, a keyed fittingwith one or more pins, a snap lock, and the like.

[0087] The radiation shield 12 can serve several other uses during theprocedure. The radiation shield 12 can contain niches for thermolucentdosimeter diodes or for scintillation dosimeters (not shown) for themeasurement of dose at the surface to provide a measure of irradiationthat is transmitted through the vein. Such an arrangement provides anindirect measure of the dose absorbed by the vein

[0088]FIG. 4 schematically shows a cross-section of an assembled device13, according to a preferred embodiment of the present invention, withits component parts. The sleeve 1 with graft 5 is shown attached to abase and pedestal 30, with housing 12 serving as a radiation shield.Base and pedestal 30 is made of any desired material. Housing 12 is madeof any desired material, preferably clear plastic. A tube 15 to an airinflator (not shown) provides means to inflate balloon 4. On the outsideof the housing 12 is the radiation safe seed module 34 with detachablesafe 6, end cap 7, outer cable sleeving 11, inner cable 10 and exemplaryradiation seed 8. The lumen 2 forms a continuous passageway from thedistal end of the detachable safe 6, which connects to the driver (notshown), through the base and pedestal 30 and into the sleeve 1. Theinner cable 10 with radiation seeds 8 at or near its tip is driven intothe lumen 2 of the sleeve 1, to deliver a radiation dose to graft 5.Typically, appropriate dosing can be achieved by one pass of the innercable 10 with radiation seeds 8 into and out of the lumen 2 of thesleeve 1. When dosing is complete, the inner cable 10 is withdrawn fromthe lumen 2 of the sleeve 1 into the lumen 2 of the detachable safe 6.The graft at this point has been suitably irradiated and is ready forremoval by the surgical staff for reimplanting in the patient.

[0089] The beta source control device 16 of FIG. 5 exemplifies anelectronic apparatus for automating the methods and devices of thepresent invention. Related afterloading devices suitable for differentuses are disclosed and claimed in U.S. Pat. No. 5,103,395, hereinincorporated by reference. The device 16 has the detachable safe 6 withattached cable and sheathing 20 wound around a drive cable capstand 21,which is rotatably driven by a drive stepping motor 22 for insertion andwithdrawal of radiation source (not shown) into the sleeve 1 with graft5 (not shown). An emergency retract handle 19 provides manual control ofthe endovascular delivery system of the present invention. A liquidcrystal display readout 17 with data entry and control panel 18 are alsoset forth in FIG. 5.

[0090] The control box for driving or inserting radiation seeds into thelumen of the sleeve is set forth in FIG. 6. The inner cable 10, whichcontains radiation seeds 8 (shown, for example, in FIGS. 3 and 4) isdriven by a cable driver pinion 24 and motor, into and out of the lumen2 of the sleeve 1 (not shown). Inner cable 10 is secured by outer cablesleeving 11. Inner cable 10 is held in place against the cable driverpinion 24 by a pinch idler 23. Pinch idler 23 rotates freely as theinner cable 10 is moved. Encoder 25 monitors the position of the innercable 10 and is part of the position control circuit.

[0091] Using the radiation seed safe module attached to acomputer-controlled stepping motor for the purpose of pushing or drivingvia cable, cam or high precision gear-driven telescoping device, such asis used to telescope a cameral lens, the source train of ⁹⁰Sr seeds,wire, or a single high-intensity source delivers the dose of irradiationin a more precisely controlled and more accurate manner than by manualmanipulation. One illustration of this apparatus is schematically shownin FIGS. 5 and 6. The computer-controlled stepping motor preventsundesirable irradiation occurring during extrusion and retraction of thesource train, which would add a small level of dose inhomogeniety alongthe length of the treated vessel graft. The stepping motor may beconnected to the push-rod by a cam or a inner cable 10.

[0092] The inner cable 10 is on a spool within the unit containing thedrive stepping motor 12. The outer cable sleeving 11 is uncoiled out ofthe motor module to be attached to the radiation seed safe module. (Theradiation seed safe module may also be kept within the central unit withonly a connector at the end of the outer cable sleeving 11). The drivestepping motor is a high speed, high precision device to deliver theradiation dose, by driving a spool of hard metal wound about which theinner cable is coiled. The inner cable extends into the outer cablesleeving and can be optionally attached to the end of the radiationsource train (not shown) within the radiation seed safe module. Theradiation seed safe module can be made so that the inner cable connectsto the source train by screw lock or permanently fixed, or otherconventional attachment means.

[0093] A variety of safety features are readily added to the devices ofthe present invention. In one model with a permanently attachedradiation seed safe module, the radiation seed safe module can bemachined so that the exit is smaller than the strontium seed casing soit cannot be retracted beyond the safe, e.g., an internal source stop 9of FIG. 3. An encoder monitors the position of the inner cable and ispart of the position control circuit. A screw clamp at each end of theradiation seed safe module prevents the radiation source from leavingthe radiation seed safe module between treatments. Another interlockwithin the radiation seed safe module prevents accidental extrusion ofthe seeds until correctly connected. The drive stepping motor has a keythat must be turned to the “on” position before it will drive the innercable into and through the lumen of the sterile sleeve. The controlpanel also has a mechanical key control to prevent accidental activationof the drive stepping motor. An optional second channel in the radiationseed safe module allows the manual or automated advancement of a checkcable prior to advancing the radiation seeds into and through the lumenof the sleeve.

[0094] An illustration of manual control of radiation treatment in themethods and devices of the present invention is set forth in FIGS. 7 and8. A knob 29 for manual grasping terminates a removable plunger 26 forinsertion and removal of radiation seeds 8. Detent plunger 27 andgrooves 28 for distance detents locks the radiation seeds 8 at thedesired position. The plunger may be removed by releasing thespring-loaded detent plunger 27. The assembled apparatus of FIG. 9 showsattachment of a housing 29, and a base and pedestal 30 suitable for adesk top procedure.

[0095] Care in preventing overstretching of the vessel graft on thesleeve 1 with balloon 4 is readily accomplished by appropriate selectionof one or more balloons from a series of graduated diameter balloons offixed size when inflated. The selected balloon or balloons can be eithera single balloon or a series of balloons. An alternative arrangement isone or more spiral balloons of appropriate size that wind around thesleeve. The balloons preferably range in size from about 15 mm maximumouter diameter to about 90 mm outer diameter, in 0.5 mm increments. Thesurgeon measures the vessel graft diameter, selects the correct sizeballoon, places the balloon on the sleeve 1 and then places the vesselgraft on the balloon. The balloon is inflated after complete placementwithin the lumen or cavity of the vessel graft. Thereafter the vesselgraft is ready for irradiation. The goal of selecting the appropriateballoon is to distend the vessel graft to almost but no more than itsnormal diameter.

[0096] Another embodiment of the present invention covers a differentclass of devices that utilize radiation administered external to andoutside of the vessel graft, as schematically illustrated by FIGS. 9A,9B and 10. This apparatus is a cylinder 32, with radiation wire orlinear arrays 34 of seeds placed longitudinally and in parallel to theinner central pin 31. A cross section of cylinder 32 is set forth inFIG. 9B. During irradiation treatment, the vessel graft mounted on thesleeve 1 is placed inside of the cylinder 32. In this fashion, beta orgamma irradiation can be administered from outside the vessel graft,i.e., an exovascular delivery of a radiation dose. The vessel graft (notshown) is mounted on a sleeve 1 and is then protected with a sterilethin-walled plastic cylinder (not shown) by inserting thereon the sleeve1 with already mounted vessel graft. Once sealed in a sterile fashionwithin the cylinder and placed within the cylinder 32, an optionalretractable shield (not shown) is removed to expose the radiationsource. Administration of the dose to the vessel graft is achieved by anumber of approaches, e.g., ⁹⁰Sr in the form of seeds, wire or foil, ortransmuted red phosphorus (³²P) combined with malleable thermoplasticmaterial. Several long linear sources (wires or seeds in a row) in theinner wall of the cylinder 32 are arranged so that a homogeneous dosedistribution is achieved where the vessel graft is treated.

[0097] Besides the cylinder 32 with linear rows of radiation sources,other configurations for radiation delivery in the present inventionreadily occur to the skilled artisan. For example, a variety of chamberslined with fabricated ⁹⁰Sr foil are suitable (not shown), includingcontainers such as a cylinder, tube, or a box. These liners may beinstalled in a configuration to achieve multiple treatments, e.g., abeta dose distribution to allow treatment of one to six vein segments.The vessel graft 5 mounted on a sleeve 1 is placed within the inside ofthe chamber, a sterile plastic liner placed therebetween to protect themounted vessel graft from microbiological contamination of the chamber.The chamber, be it a cylinder, tube, or box may be hinged and the“clam-shell or “lid” closed to administer the dose of therapeuticirradiation. The simplest design is a ⁹⁰Sr foil-lined cylinder, sealedat one end with a thin center-post (not shown). Thin 0.5 mm sterileplastic liners can be inserted onto the sleeve and over the post. Overthe post, the vessel graft on a sleeve with optional balloon is insertedand left in place for the length of time required to administer thedesired dose.

[0098] In one embodiment, a strontium source is utilized to administer atherapeutic dose of beta irradiation between about 6.0 to about 18.00Gy, preferably between about 10.0 to about 14.0 Gy. A segment ofsaphenous vein (usually 15 cm long but sometimes longer) is irradiatedfrom within the lumen of the vein via an apparatus that houses andprovides endovascular delivery of ⁹⁰Sr radiation sources. The sourcesare uncovered by a retractable shield or are protruded from a housingthat serves as a radiation shield.

[0099] The methods and devices of the present invention are adaptable toa variety of beta and gamma irradation sources, including, but notlimited to,⁹⁰Sr, ⁹⁰Y, ¹⁰⁶Ru, ³²P, ¹⁹²Ir, ¹²⁵I, ¹⁹⁸Au, or ¹⁰³Pd. Onepreferred radiation source is ⁹⁰Sr. Preferred dosage ranges are betweenabout 1.0 Gy and about 60.0 Gy, preferably between about 3.0 Gy andabout 30.0 Gy, most preferably between about 6.0 Gy and about 20.0 Gy.Selecting the appropriate isotope and dosage is within the skill of theart. The desired exposure time is readily calculated for a given graftdiameter, radioisotope, and sleeve geometry and size. The outwardconfiguration of the radiation source is typically in the form of aseed, a piece of foil, a ring, a pin, or a rod.

[0100] The selected radioactive material may be contained within glass,foil, or ceramics, or, alternatively, within a powder or liquid medium,such as microparticles in liquid suspension. When solid materials areused, the preferred outer diameter of the material is approximately 0.5mm, allowing it to be inserted into the central lumen of the veinsleeve. Such radioactive materials may be formed into pellets, spheres,and/or rods in order to be placed into the chamber of the treatingelement.

[0101] Various alternative treating elements may also be used to containthe radioactive material without departing from the present invention.For example, the treating elements may be toroidal, spherical, or in theform of elongated rings, and in such configurations, the radioactivematerial may be actually impregnated in a metal and formed into thedesired shape. Alternatively, a radioactive powder may be fired to fusethe material so that it may be formed into the desired shape, which maythen be encapsulated in metal, such as titanium, stainless steel orsilver, or in plastic, as by dipping in molten or uncured plastic. Instill another embodiment, the treating elements may be formed from aceramic material which has been dipped in a radioactive solution In astill further alternative, the treating elements may be constructed inthe form of two piece hollow cylindrical capsules having alarger-diameter half with a central cavity and a smaller-diameter halfalso having a central cavity, the smaller half slidably received withinthe larger half and bonded or welded to form the capsule structure.

[0102] The methods and devices of the present invention are suitable forany autologous coronary bypass conduit, provided that the bypass conduitis large enough. Suitable veins and arteries include, but are notlimited to the long saphenous vein, the short saphenous vein, thecephalic vein, the brachiocephalic vein, or radial artery.

EXAMPLE Ex Vivo Irradiation of Saphenous Vein Graft During CoronaryArtery Bypass Surgery

[0103] The technique of ex vivo irradiation requires few modificationsfrom the conventional bypass coronary artery procedure. The patient isbrought into the surgery room. Monitors are attached and intravenouslines are started. The patient is put to sleep. Once the patient isasleep, the surgeon performs a median sternotomy or in some cases alateral mini-thoractomy. The pericardium is incised and the beatingheart is exposed. Canulas are positioned into the right atrium and intothe aorta. The heart is stopped with cardioplege solution and the bypassperfusion pump is started to circulate blood through the body in theplace of the beating heart. Incisions are made on the inner aspect ofone or both legs. The saphenous vein is dissected from the fatty tissuesof the medial leg. The vein is checked for leaks by distending withsaline or thereafter sterile fluid under pressure. Branching venules areligated and leaks are repaired. The vein is cut to a 15 cm length. Afterthe vein is resected, inspected, and repaired, a radiation treatmentsleeve is selected by the surgeon based upon the diameter of thesaphenous vein when it was filled with blood when still in the patient'sleg. After the correct sleeve is selected, it is placed into the lumenof the graft so that the vein is “impaled” upon the sleeve. Then, thesleeve mounted with saphenous vein is attached via adaptor to the baseand pedestal with clear plastic hood. Then, a detachable safe(containing radiation seeds) with mechanical or automated control unitsis attached via adaptor to the sleeve mounted with saphenous vein. Atreatment time and treatment plan are selected from an atlas or devisedupon a miniature treatment planning computer for a treatment upon thesize of the treatment sleeve. Then, after the clear plastic hood islowered, radiation seeds of ⁹⁰Sr are placed by remote control into thesleeve mounted with saphenous vein, and thus in effect into the lumen ofthe saphenous vein graft segment. A dose of 20.0 Gy is administered. Theradiation seeds are then withdrawn by remote control from the lumen ofthe saphenous vein graft segment. The vein is removed from the sleeveand handed to the surgeon. Then, one end of the vein is sewn to anincision into the aorta and the other end is sewn to the coronary arteryjust beyond an angiographically detected blockage of the artery.

[0104] This procedure is repeated until all coronary arteries withsignificant blockages are bypassed, so that blood coming through thesaphenous vein graft from the aorta to the coronary artery bypasses theblocked or occluded areas to perfuse the heart muscle. Then, the heartbeat is restarted, the perfusion pump is removed, the patient's heartbegins to circulate his own blood. Chest tubes are placed through thechest wall to drain any blood into the thoracic cavity to a sealedcollecting system outside of the patient. The chest incision is thenclosed with sternal wires and with sutures. The patient is taken thecardiovascular intensive care unit and allowed to awaken.

[0105] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations, modifications ordeletions as come within the scope of the following claims and itsequivalents.

1. A method of reducing overgrowth of vascular repair tissue inautologous coronary bypass conduit grafts, comprising the steps of: (a)providing a graft harvested ex vivo from a mammal; (b) subjecting thegraft to irradiation with a dose effective for reducing fibrointimalproliferation or neointimal hyperplasia, to give a treated graft; and(c) surgically implanting the treated graft into same mammal.
 2. Themethod of claim 1, wherein the coronary bypass conduit graft is removedfrom the long saphenous vein, the short saphenous vein, the cephalicvein, the brachiocephalic vein, or radial artery.
 3. The method of claim1, wherein the irradiation is beta irradiation from within the lumen ofthe graft.
 4. The method of claim 1, wherein the irradiation comes fromX-rays from a micro X-ray source within the lumen of the graft.
 5. Themethod of claim 1, wherein the irradiation comes from the gamma emittingradionuclide ¹²⁵I.
 6. The method according to claim 1, wherein themammal is a human.
 7. The method according to claim 1, wherein the doseis limited to a range of between about 1.0 Gy and about 60.0 Gy.
 8. Themethod according to claim 1, wherein the dose is limited to a range ofbetween about 3.0 Gy and about 30.0 Gy.
 9. The method according to claim1, wherein the dose is limited to a range of between about 6.0 Gy andabout 20.0 Gy.
 10. The method according to any of claims 1-3, 6-9,wherein the radiation source is ⁹⁰Sr.
 11. A method of reducingfibrointimal proliferation or neointimal hyperplasia in autologouscoronary bypass vein grafts, comprising the steps of: (a) providing avein harvested ex vivo from a human, said vein selected from the longsaphenous vein and the short saphenous vein; (b) subjecting the vein tobeta irradiation from within the lumen of the vein, with a doseeffective for reducing fibrointimal proliferation or neointimalhyperplasia, said dose ranging from between about 6.0 Gy and about 20.0Gy of ⁹⁰Sr, to give a treated vein; and (c) surgically implanting thetreated vein into same human.
 12. A device for irradiating ex vivoautologous coronary bypass conduit grafts of a mammal, comprising (a) asterile sleeve insertable ex vivo into the lumen of the graft; and (b) aradiation source capable of delivering a dose effective for reducingfibrointimal proliferation or neointimal hyperplasia in the graft, saidsource insertable into said sleeve for endovascular delivery of theradiation dose to the graft.
 13. The device of claim 12, wherein thecoronary bypass conduit graft is removed from the long saphenous vein,the short saphenous vein, the cephalic vein, the brachiocephalic vein,or radial artery.
 14. The device of claim 12, wherein the radiationsource produces beta irradiation.
 15. The device of claim 12, whereinthe radiation source produces X rays from a micro X-ray source.
 16. Thedevice of claim 12, wherein the radiation source is the gamma emittingradionuclide ¹²⁵I.
 17. The device of claim 12, wherein the mammal is ahuman.
 18. The device of claim 12, wherein the radiation source deliversa dose of between about 1.0 Gy and about 60.0 Gy.
 19. The device ofclaim 12 wherein the radiation source delivers a dose of between about3.0 Gy and about 30.0 Gy.
 20. The device of claim 12 wherein theradiation source delivers a dose of between about 6.0 Gy and about 20.0Gy.
 21. The device according to, any of claims 13-14, 18-20, wherein theradiation source is ⁹⁰Sr.
 22. A device for irradiating ex vivo anautologous coronary bypass vein graft in a human, comprising (a) asterile sleeve insertable ex vivo into the lumen of the vein graft; and(b) a radiation source capable of delivering a dose effective forreducing fibrointimal proliferation or neointimal hyperplasia in thevein graft, said source comprising radiation seeds of ⁹⁰Sr, said sourceinsertable into said sleeve for endovascular delivery of the radiationdose to the vein graft, said dose ranging from between about 6.0 Gy andabout 20.0 Gy.
 23. A device for irradiating ex vivo an autologouscoronary bypass conduit graft of a mammal, comprising (a) a sterilesleeve for holding ex vivo the graft during its irradiation, wherein thesleeve is insertable ex vivo into the graft lumen; (b) a radiation seedsafe module attached, with or without fixed or detachable adaptor means,to the sleeve with locking or screwing means, said module containing aradiation source capable of being driven into and through the lumen ofthe sterile sleeve to provide endovascular delivery of a radiation doseto the graft, said radiation dose suitable for reducing fibrointimalproliferation or neointimal hyperplasia in the graft; and (c) aradiation shield attached at or near the junction of the sleeve and theradiation seed safe module.
 24. The device of claim 23, wherein thecoronary bypass conduit graft is removed from the long saphenous vein,the short saphenous vein, the cephalic vein, the brachiocephalic vein,or radial artery.
 25. The device of claim 23, wherein the radiationsource produces beta irradiation.
 26. The device of claim 23, whereinthe radiation comes from X rays from a micro X ray source.
 27. Thedevice of claim 23, wherein the radiation source is the gamma emittingradionuclide ¹²⁵I.
 28. The device of claim 23, wherein the mammal ishuman.
 29. The device of claim 23, wherein the radiation sourcecomprises radiation seeds of ⁹⁰Sr.
 30. The device of claim 23, whereinthe radiation dose is limited to the range between about 1.0 Gy andabout 60.0 Gy.
 31. The device of claim 23 wherein the radiation dose islimited to the range between about 3.0 Gy and about 30.0 Gy.
 32. Thedevice of claim 23 wherein the radiation dose is limited to the rangebetween about 6.0 Gy and about 20.0 Gy.
 33. A device for betairradiating ex vivo an autologous vein graft of a human, comprising (a)a sterile sleeve for holding ex vivo the graft during its irradiation,wherein the sleeve is insertable ex vivo into the graft lumen; (b) aradiation seed safe module attached, with or without fixed or detachableadaptor means, to the sleeve with locking or screwing means, said modulecontaining a radiation source comprising one or more radiation seeds of⁹⁰Sr capable of being driven into and through the lumen of the sleeve toprovide endovascular delivery of a radiation dose to the graft, saidradiation dose suitable for reducing fibrointimal proliferation orneointimal hyperplasia in the graft, said radiation dose between about6.0 Gy and about 20.0 Gy; and (c) a radiation shield attached at or nearthe junction of the sleeve and the radiation seed safe module.
 34. Adevice for irradiating ex vivo autologous coronary bypass conduit graftsof a mammal, comprising (a) a sterile slender elongated means insertableex vivo into the lumen of the graft, for the purpose of mounting andpositioning the graft; (b) a cylinder with one or more attachedradiation sources, said elongated means with mounted graft insertableinto the inside of the cylinder for exovascular delivery of theradiation dose to the graft, said radiation sources capable ofdelivering a dose effective for reducing fibrointimal proliferation orneointimal hyperplasia in the graft.